RARE Daily

Ultragenyx Reports Positive Top-Line Results from Phase 3 Study of Gene Therapy for GSDIa

May 31, 2024

Rare Daily Staff

Ultragenyx Pharmaceutical reported positive topline results from a late stage study evaluating its investigational gene therapy DTX401 for the treatment of patients aged eight years and older with glycogen storage disease type Ia.

Glycogen storage disease type Ia (GSDIa) is a serious inherited glycogen storage caused by a defective gene coding for the enzyme G6Pase-α, and resulting in the inability to regulate blood sugar. Hypoglycemia in patients with GSDIa can be life-threatening, while the accumulation of the complex sugar glycogen in certain organs and tissues can impair the ability of these tissues to function normally. If chronically untreated, patients can develop severe lactic acidosis, progress to renal failure, and potentially die in infancy or childhood. There are no approved pharmacologic therapies. An estimated 6,000 patients worldwide are affected by GSDIa.

DTX401 is an investigational AAV8 gene therapy designed to deliver stable expression and activity of G6Pase-α under control of the native promoter to allow the treated liver cells to respond to normal hormonal signals intended to manage glucose, including insulin, glucagon and cortisol.

GlucoGene, a 48-week randomized, double-blind, placebo-controlled phase 3 study that treated 46 patients aged eight years and older with DTX401 or placebo, achieved its primary endpoint, demonstrating that treatment with DTX401 resulted in a statistically significant and clinically meaningful reduction in daily cornstarch intake compared with placebo at Week 48. The mean percent reduction was 41.3 percent in the DTX401 group compared with 10.3 percent in the placebo group at Week 48. Across patients treated with DTX401, the mean reduction in cornstarch continued to decline over the 48-week period. In the treatment group, all patients achieved a reduction in cornstarch, with 68 percent achieving ≥30 percent reduction and 37 percent achieving ≥50 percent reduction compared to the placebo group, which achieved the same reductions in 13 percent and 4 percent of patients, respectively, at Week 48.

“This is an incredible milestone for the DTX401 program. These clinically important and statistically significant results are consistent with our phase 1/2 findings, and the continued improvement in these treated patients reflects the acquired ability to break down glycogen as a source of endogenous glucose from their treated livers,” said Eric Crombez, chief medical officer at Ultragenyx.

The study also successfully met key secondary endpoints of reduction in the number of cornstarch doses per day and maintenance of glucose control at Week 48. Treatment with DTX401 resulted in a mean reduction of 1.1 cornstarch doses per day in the DTX401 treatment group compared with a mean reduction of 0.2 in the placebo group. Patients in the DTX401 group also showed significant improvement in both frequency and quantity of nighttime cornstarch dosing compared with the placebo group. This blinded study established non-inferiority of glucose control between the study groups while the treatment group significantly reduced daily cornstarch intake.

The Patient Global Impression of Change (PGIC) at Week 48 showed a median score of 2.0 (moderately improved) for the DTX401 treatment group and 1.0 (minimally improved) for the placebo group. Moderately or higher improved PGIC scores correlated with a ≥30 percent reduction in total daily cornstarch intake indicating that this is a clinically meaningful threshold for patients.

“With these phase 3 results, the significant reduction in cornstarch intake with continued management of glucose control has the potential to offer meaningful benefit to patients while improving their quality of life on a daily basis,” said Rebecca Riba-Wolman, director of the Glycogen Storage Disease Program & Disorders of Hypoglycemia at Connecticut Children’s Medical Center/University of Connecticut Medical School and study investigator. “GSDIa is a disease that never takes a break, where you must constantly think about your own, or your child’s, safety and risk of severe low blood sugar and acidosis throughout the day and especially at night. A treatment that can improve these daily concerns for people with GSDIa without significant risks is essential.”

The study demonstrated an acceptable and expected safety profile for DTX401 consistent with phase 1/2 study results. Anticipated vector-induced hepatic effects were all non-serious and manageable with a prophylactic corticosteroid regimen. No AAV8 class effects of dorsal root ganglion toxicity or thrombotic microangiopathy were observed in the study through Week 48.

After study completion, patients will be offered enrollment into a Disease Monitoring Program where they will be followed for at least 10 years post-DTX401 infusion.

Full 48 Week data from the phase 3 study will be presented at a scientific conference later this year. These results will be discussed with regulatory authorities to support a marketing application in 2025.

DTX401 has been granted orphan drug designation, regenerative medicine advanced therapy (RMAT) designation and Fast Track designation from the U.S. Food and Drug Administration, as well as PRIority MEdicines (PRIME) and orphan drug designation from the European Medicines Agency.

Photo: Eric Crombez, chief medical officer at Ultragenyx

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